Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome

Zhang, Anju; Zheng, Chengyun; Hou, Mi; Lindvall, Charlotta; Li, Kejun; Erlandsson, Fredrik; Björkholm, Magnus; Gruber, Astrid; Blennow, Elisabeth; Xu, Dawei

doi:10.1086/374565

Cited by 65 publications

(44 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2, although harboring much stronger telomere signals than their adjacent normal cells, lacked detectable hTERT protein, suggesting the activation of an alternative mechanism for telomere lengthening (Figure 3). Telomere hybridization was performed, and the maximum intensity projections of the acquired images were analysed using the IMP image-processing software (the Center for Image Analysis at Uppsala University, Uppsala, Sweden) (Zhang et al, 2003). Telomere signals in 10 nuclei from normal or different pathological regions were measured separately, and then normalized by DAPI fluorescence intensity in corresponding areas as described van Heek et al, 2002).…”

Section: Telomere Attrition In Cervical Carcinogenesismentioning

confidence: 99%

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

et al. 2004

Self Cite

View full text Add to dashboard Cite

Although human papillomavirus (HPV) has been defined as the pathogen for cervical carcinomas, molecular events underlying the oncogenic process are unclear. As telomere dysfunction-mediated chromosomal instability and telomerase activation have been suggested as key events in carcinogenesis, we dissected the dynamic changes in telomere length, checkpoint response, and temporal profile of telomerase expression during the evolution from precursor lesions (cervical intraepithelial neoplasia, CINs) to invasive cancers of the uterine cervix in sequential samples from 16 patients. Telomeres were significantly shortened in all CIN samples and no further substantial attritions occurred in most cases with the acquisition of malignant phenotype. Very short telomeres were coupled with constitutive activation of the DNA damage response pathway (Chk2 phosphorylation) and increased cellular proliferation in those cervical specimens. Telomerase reverse transcriptase (hTERT) expression was preferably induced at advanced CINs or invasive cancers. The present finding demonstrates that excessive telomere shortening predominantly occurs in the early carcinogenesis of the uterine cervix largely prior to telomerase activation. Widespread over-erosion of telomeres or telomere dysfunction in very early stages of cervical tumorigenesis might fuel transformation processes by driving chromosomal instability.

show abstract

Section: Telomere Attrition In Cervical Carcinogenesismentioning

confidence: 99%

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

et al. 2004

Self Cite

View full text Add to dashboard Cite

show abstract

“…Monosomy for a contiguous stretch of genes at the distal portion of chromosome 5p is associated with CdCS. Several genes in the region including SEMA5A, CTNND2, and TERT are of particular interest because their products play major roles during embryonic and neuronal development [Simmons et al, 1998;Medina et al, 2000;Zhang et al, 2003]. The SEMA5A gene encodes a membrane protein with a semaphorin domain and several thrombospondin type-1 repeats, and acts as a signaling molecule that regulates axonal guidance and neuronal migration during development.…”

Section: Discussionmentioning

confidence: 99%

“…The telomerase reverse transcriptase (TERT) gene is localized at 5p15.33 and encodes the rate-limiting component of telomerase complex essential for telomere length maintenance and sustained cell proliferation [Zhang et al, 2003]. It has been demonstrated that individuals with CdCS who are haploinsufficient for TERT have shorter telomere length compared to age-matched unaffected individuals [Zhang et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

“…Multiple chromosomal locations have been implicated in intellectual disability and microcephaly, including 5p15.31 [Rossi et al, 2005], 5p15.2, 5p15.1, and 5p13p14 [Overhauser et al, 1994;Gersh et al, 1995;Mainardi et al, 2001]. Several genes on 5p, including SEMA5A (Semaphorin 5A), CTNND2 (deltacatenin), and TERT (human telomerase reverse transcriptase), have been studied in association with autism spectrum disorder, intellectual disability, schizophrenia, or altered fetal development [Medina et al, 2000;Zhang et al, 2003;Harvard et al, 2005;Vrijenhoek et al, 2008;Weiss et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

Zhang

Willing

Grange

et al. 2015

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.

show abstract

“…Since the corresponding region (Rp11-79L17) was conserved in patient 3, this gene might be essential for mental conditions. Zhang et al (2003) reported that the deletion of the hTERT gene located on 5p15.33 in 5p-syndrome might impair normal fetal development. However, we have shown that patients 1, 4, and 5, who lacked IUGR, as well as those with IUGR, lost hTERT.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

Genotype-phenotype correlation of 5p- syndrome: pitfall of diagnosis

et al. 2004

View full text Add to dashboard Cite

To clarify the genotype-phenotype correlation of 5p-syndrome, FISH analyses were performed for six patients by using a series of probes spanning 5p13.1-p15.33. Genotypically, break points of deletion were quite different. Three of the six patients were diagnosed as interstitial deletion on chromosome 5p by G-banding method and FISH analysis; however, all of them proved to be entire distal deletions of 5p caused by unbalanced chromosomal translocations. Furthermore, one 5p-syndrome patient was diagnosed only by the FISH analysis using a single probe but not by ordinary chromosomal analyses. Therefore, when ordinary chromosomal analysis cannot detect any deletion in a patient who is phenotypically suspected of 5p-syndrome, multiple FISH analysis or parental chromosomal analysis would be needed for correct diagnosis. Interestingly, one patient with terminal deletion between 5p15.31-pter lacks mental retardation and cat-like crying, indicating that this region might not be responsible for those cardinal features of 5p-syndrome. Further studies on genotype-phenotype correlation will help us better understand 5p-syndrome and also determine functional mapping of the 5p region.

show abstract

Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome

Cited by 65 publications

References 42 publications

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

Genotype-phenotype correlation of 5p- syndrome: pitfall of diagnosis

Contact Info

Product

Resources

About